Fluoxetine exposure for more than 2 days decreases the neuronal plasticity mediated by CRMP2 in differentiated PC12 cells

Recent studies indicate that antidepressants treatment restores neuronal plasticity. In contrast, some researchers claim that serotonergic antidepressants, including fluoxetine (FLU), may exacerbate neuronal plasticity, which is contradictory and rarely studied. Since almost those studies exposed cells with drugs for 1-2 days as treatment models of antidepressants, it is possible that FLU exposure for longer periods would have opposite effects on neuronal plasticity.In the present study, we examined the effects of FLU exposure (up to 3 days) on the neuronal plasticity in differentiated PC12 cells. The cell viability shown a slight decrease at day 2 (93.5 ± 3.5 %), followed by a highly significant decrease at day 3(71.4 ± 4.4 %). As previously reported, neuronal plasticity was significantly upregulated by FLU exposure at day 1. However, the neurite length, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos mRNA were inhibited with FLU exposure at day 3. Similarly, the expression of tubulin, which play important roles in the neuronal plasticity, was the same result. Furthermore, we found α-tubulin interacted with collapsing response mediator protein 2(CRMP2), which is related to neuronal plasticity, and the regulation of CRMP2 activity influenced the neurite length, Arc, c-Fos and tubulin expression.The results demonstrated that neuronal plasticity was increased by FLU exposure at day 1, but exposure with FLU for more than 2 days had opposite effect on it. The reduction in neuronal plasticity with FLU exposure for more than 2 days might be involved in some aspects of the therapeutic effect of antidepressant on depression.